The invention relates to benzenesulfonamides and derivatives thereof.
MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade. The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above-mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.
Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK1 and MEK2) which then activates MAP kinase, ERK (ERK1 and ERK2). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S218 and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine, Y185, and a threonine residue, T183, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase, ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found.
The invention features a compound having the formula (I) below: 
W is OR1, NR2OR1, NRARB, NR2NRARB, or NR2(CH2)2-4NRARB. R1 is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (phenyl)C1-4 alkyl, (phenyl)C3-4 alkenyl, (phenyl)C3-4 alkynyl, (C3-8 cycloalkyl)-C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, (C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (C3-8 heterocyclic radical)C3-4 alkenyl, (C3-8 heterocyclic radical)C3-4 alkynyl, or (CH2)2-4NRARB. R2 is H, phenyl, C1-4 alkyl, C3-4 alkenyl C3-8 alkynyl, C3-8 cycloalkyl, or (C3-8 cycloalkyl)C1-4 alkyl. RA is H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (C3-8 cycloalkyl)C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, (C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C1-4 alkyl, (aminosulfonyl)C1-6 alkyl, (aminosulfonyl)C3-6 cycloalkyl, or [(aminosulfonyl)C3-6 cycloalkyl]C1-4 alkyl. R8 is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, or C6-8 aryl. R3 is H, F, Cl, Br, or NO2. R4 is H or F. R5 is H, methyl or Cl. R6 is H, C1-4 alkyl, hydroxyethyl, hydroxypropyl, (CH2)2-4(NRCRD), phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or CH2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. R7 is H, C1-4 alkyl, hydroxyethyl, hydroxypropyl, (CH2)2-4(NRCRD), phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or CH2Arxe2x80x2, where Arxe2x80x2 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. Each of RC and RD is independently selected from H, C1-6 alkyl, C3-4 alkenyl, C3-4 alkynyl, C3-6 cycloalkyl, C3-6 heterocyclic radical, and phenyl. NRCRD can also be selected from morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl. Each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, hydroxy, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C1-2 alkyl, hydroxy, amino, and NO2. The invention also features pharmaceutically acceptable salts and C1-7 esters thereof.
Preferred compounds include PD 297764, 3,4-Difluoro-2-(4-iodo-phenylamino)-N-methoxy-5-(4-pyridin-2-yl-piperazine-1-sulfonyl)-benzamide; PD 297765, N-Allyloxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(4-methyl-piperazine-1-sulfonyl)-benzamide; PD297766, N-Allyloxy-5-[(2-diethylamino-ethyl)-methyl-sulfamoyl]-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; PD297767, N-Allyloxy-5-[(3-dimethylamino-propyl)-methyl-sulfamoyl]-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; PD297768, N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(4-methyl-piperazine-1-sulfonyl)-benzamide; PD297769, N-Cyclopropylmethoxy-5-[(2-diethylamino-ethyl)-methyl-sulfamoyl]-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; PD297770, N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-[methyl-(2-pyridin-2-yl-ethyl)-sulfamoyl]-benzamide; PD297771, N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(4-pyridin-2-yl-piperazine-1-sulfonyl)-benzamide; PD297772, 5-[Benzyl-(2-dimethylamino-ethyl)-sulfamoyl]-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; PD297773, 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-5-(4-pyridin-2-yl-piperazine-1-sulfonyl)-benzamide; and PD297774, 1-[5-Allyloxycarbamoyl-2,3-difluoro-4-(4-iodo-2-methyl-phenylamino)-benzenesulfonyl]-piperidine-3-carboxylic acid amide.
The invention also relates to a pharmaceutical composition including (a) a compound of formula (I) and (b) a pharmaceutically-acceptable carrier.
The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis. Other aspects of the invention include methods for treating MEK-related (including ras-related) cancers, whether solid or hematopoietic. Examples of cancers include colorectal, cervical, breast, ovarian, brain, acute leukemia, gastric, non-small cell lung, pancreatic and renal cancer. Further aspects of the invention include methods for treating or reducing the symptoms of xenograft (cell(s), skin, limb, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy), hepatomegaly, cardiomegaly, stroke (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma, and Alzheimer""s disease. Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis B virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). These methods include the step of administering to a patient in need of such treatment, or suffering from such a disease or condition, a pharmaceutically-effective amount of a disclosed compound or pharmaceutical composition thereof.
The invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such as cisplatin, 5-fluorouracil or 5-fluoro-2-4 (1H,3H)-pyrimidinedione (5FU), flutamide, and gemcitabine. The chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.
The invention also features synthetic methods and synthetic intermediates disclosed herein.
Other aspects of the invention are provided in the description, examples, and claims below.
The invention features benzenesulfonamide compounds, pharmaceutical compositions thereof, and methods of using such compounds and compositions.
According to one aspect of the invention, the compounds are MEK inhibitors. MEK inhibition assays include the cascade assay for inhibitors of MAP kinase pathway described at column 6, line 36 to column 7, line 4 of U.S. Pat. No. 5,525,625 and the in vitro MEK assay at column 7, lines 4-27 of the same patent, the entire disclosure of which is incorporated by reference (see also Examples 5-10 below).
A. Terms
Certain terms are defined below and by their usage throughout this disclosure.
Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1-dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Alkyl groups can be substituted with 1, 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Specific examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl.
Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example. Examples of alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2xe2x80x2-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2-propenyl.
In formula (I), alkenyls and alkynyls can be C2-4 or C2-8, and are preferably C3-4 or C3-8.
More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents. According to formula (I), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl. R1 thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth. Similarly, RA includes hydroxyalkyl and aminoaryl, and R8 includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.
Heterocyclic radicals, which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl.
Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC50 for MEK 1 or MEK 2 that is at least one-fiftieth ({fraction (1/50)}) that of its IC50 for one of the above-named other enzymes. Preferably, a selective inhibitor has an IC50 that is at least {fraction (1/100)}, more preferably {fraction (1/500)}, and even more preferably {fraction (1/1000)}, {fraction (1/5000)}, or less than that of its IC50 or one or more of the above-named enzymes.
B. Compounds
One aspect of the invention features disclosed compounds shown in formula (I) in the Summary section.
Examples of compounds of formula (I) have structures wherein: (a) the sulfamoyl group is meta to W(CO)xe2x80x94 and para to the bridging NH; (b) the sulfamoyl group is para to W(CO)xe2x80x94 and meta to the bridging NH; (c) R4 is fluoro; (d) R3 is fluoro; (e) R3 is H; (f) W is OH; (g) W is NR2OR1; (h) each of R3 and R4 is fluoro; (i) R1 has at least one hydroxy substituent; (k) R1 is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl, (C3-5 cycloalkyl)C1-2 alkyl, (C3-5 heterocyclic radical)-C1-2 alkyl, or (CH2)2-4NRARB; (I) R1 is H or (C3-4 cycloalkyl)C1-2 alkyl; (m) R2 is H, methyl, C2-4 alkynyl, C3-5 cycloalkyl, or (C3-5 cycloalkyl)methyl; (n) RA is H, methyl, ethyl, isobutyl, hydroxyethyl, hydroxypropyl, cyclopropylmethyl, cyclobutylmethyl, C3-4 alkynyl, phenyl, 2-piperidin-1-yl-ethyl, 2,3-dihydroxy-propyl, 3-[4-(2-hydroxyethyl)-piperazin-1-yl]-propyl, 2-pyrrolidin-1-yl-ethyl, or 2-diethylamino-ethyl; and RB is H; or where RB is methyl and RA is phenyl; (O)R7 is (CH2)2-4(NRCRD); (p) NRCRD is selected from morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl; (q) RC is methyl, ethyl, hydroxyethyl, or hydroxypropyl; (r) R5 is methyl or chloro; (s) RD is methyl, ethyl, hydroxyethyl, or hydroxypropyl; (t) or combinations thereof, such as wherein each of RC and RD is methyl or ethyl.
Preferably, where one of R1, R2, RA, RB, RC, or RD is an alkenyl or alkynyl group, the double or triple bond, respectively, is not adjacent the point of attachment. For example, where W is NR2OR1, R2 is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1-ynyl or but-1-enyl.
Examples of compounds of formula (I) include: 2-(2-chloro-4-iodo-phenylamino)-4-sulfamoyl-benzoic acid; 2-(2-chloro-4-iodo-phenylamino)-N-hydroxy-4-sulfamoyl-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-sulfamoyl-benzamide; 2-(2-chloro-4-iodo-phenylamino)-4-(2-morpholin-4-yl-ethylsulfamoyl)-benzoic acid; 2-(2-chloro-4-iodo-phenylamino)-N-hydroxy-4-(2-morpholin-4-yl-ethylsulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-(2-morpholin-4-yl-ethylsulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-sulfamoyl-benzoic acid; 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-5-sulfamoyl-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-sulfamoyl-benzamide; 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-(2-morpholin-4-yl-ethylsulfamoyl)-benzoic acid; 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-5-(2-morpholin-4-yl-ethylsulfamoyl)-benzamide; and 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-(2-morpholin-4-yl-ethylsulfamoyl)-benzamide.
Other examples include 5-[bis-(4-methoxy-benzyl)-sulfamoyl]-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid; and 2-(2-chloro-4-iodo-phenylamino)-5-dimethylsulfamoyl-3,4-difluoro-benzoic acid methyl ester.
Additional examples include 5-(bis-pyridin-3-ylmethyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-phenylamino)-benzoic acid; 5-(bis-pyridin-3-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(methyl-pyridin-3-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluro-2-4-iodo-phenylamino)-5-[(pyridin-3-ylmethyl)-sulfamoyl]-benzamide; N-cyclopropylmethoxy-5-[(3-diethylamino-propyl)-pyridin-3-ylmethyl-sulfamoyl]-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-3-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-5-(ethyl-pyridin-3-ylmethyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-3-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; 5-(bis-pyridin-2-ylmethyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-phenylamino)-benzoic acid; 5-(bis-pyridin-2-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(methyl-pyridin-2-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-[(pyridin-2-ylmethyl)-sulfamoyl]-benzamide; 5-(bis-pyridin-3-ylmethyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-(bis-pyridin-3-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-(methyl-pyridin-3-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-[(pyridin-3-ylmethyl)-sulfamoyl]-benzamide; N-cyclopropylmethoxy-5-[(3-diethylamino-propyl)-pyridin-3-ylmethyl-sulfamoyl]-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-3-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-5-(ethyl-pyridin-3-ylmethyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-3-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-(bis-pyridin-2-ylmethyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-(bis-pyridin-2-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-(methyl-pyridin-2-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-[(pyridin-2-ylmethyl)-sulfamoyl]-benzamide; 5-(bis-pyridin-3-ylmethyl-sulfamoyl)-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid, 5-(bis-pyridin-3-ylmethyl-sulfamoyl)-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-(methyl-pyridin-3-ylmethyl-sulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(pyridin-3-ylmethyl)-sulfamoyl]-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-5-[(3-diethylamino-propyl)-pyridin-3-ylmethyl-sulfamoyl]-3,4-difluoro-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-3-ylmethyl-sulfamoyl]-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-5-(ethyl-pyridin-3-ylmethyl-sulfamoyl)-3,4-difluoro-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-3-ylmethyl-sulfamoyl]-benzamide; 5-(bis-pyridin-2-ylmethyl-sulfamoyl)-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid; 5-(bis-pyridin-2-ylmethyl-sulfamoyl)-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-(methyl-pyridin-2-ylmethyl-sulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(pyridin-2-ylmethyl)-sulfamoyl]-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-2-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-2-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; 5-(benzyl-pyridin-2-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-[(pyridin-4-ylmethyl)-sulfamoyl]-benzamide; N-cyclopropylmethoxy-5-(ethyl-pyridin-4-ylmethyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(methyl-pyridin-4-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-4-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-4-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(methyl-phenyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-phenylsulfamoyl-benzamide; N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-phenylamino)-5-(pyridin-3-ylsulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-2-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-2-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-(benzyl-pyridin-2-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-[(pyridin-4-ylmethyl)-sulfamoyl]-benzamide; N-cyclopropylmethoxy-5-(ethyl-pyridin-4-yl methyl-sulfamoyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-(methyl-pyridin-4-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-4-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-4-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-(methyl-phenyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-5-(pyridin-3-ylsulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-2-ylmethyl-sulfamoyl]-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-2-ylmethyl-sulfamoyl]-benzamide; 5-(benzyl-pyridin-2-ylmethyl-sulfamoyl)-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(pyridin-4-ylmethyl)-sulfamoyl]-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-5-(ethyl-pyridin-4-ylmethyl-sulfamoyl)-3,4-difluoro-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-(methyl-pyridin-4-ylmethyl-sulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl)-pyridin-4-ylmethyl-sulfamoyl]-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)-pyridin-4-ylmethyl-sulfamoyl]-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-(methyl-phenyl-sulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-phenylsulfamoyl-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-(pyridin-3-ylsulfamoyl)-benzamide; N-cyclopropylmethoxy-2-(4-iodo-phenylamino)-4-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-2-(4-iodo-phenylamino)-4-(pyridin-3-ylsulfamoyl)-benzamide; N-cyclopropylmethoxy-2-(4-iodo-phenylamino)-4-[(pyridin-3-ylmethyl)-sulfamoyl]-benzamide; 4-(bis-pyridin-3-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-4-[(2-hydroxy-ethyl)-pyridin-4-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-2-(4-iodo-phenylamino)-4-(methyl-pyridin-3-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-4-[(3-diethylamino-propyl)-pyridin-3-ylmethyl-sulfamoyl]-2-(4-iodo-phenylamino)-benzamide; N-cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-(pyridin-3-ylsulfamoyl)-benzamide; N-cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-[(pyridin-3-ylmethyl)-sulfamoyl]-benzamide; 4-(bis-pyridin-3-ylmethyl-sulfamoyl)-N-cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-4-[(2-hydroxy-ethyl)-pyridin-4-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-(methyl-pyridin-3-ylmethyl-sulfamoyl)-benzamide; N-cyclopropylmethoxy-4-[(3-diethylamino-propyl)-pyridin-3-ylmethyl-sulfamoyl]-2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-phenylsulfamoyl-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-(pyridin-3-ylsulfamoyl)-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-[(pyridin-3-ylmethyl)-sulfamoyl]-benzamide; 4-(bis-pyridin-3-ylmethyl-sulfamoyl)-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-[(2-hydroxy-ethyl)-pyridin-4-ylmethyl-sulfamoyl]-benzamide; 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-(methyl-pyridin-3-ylmethyl-sulfamoyl)-benzamide; and 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-[(3-diethylamino-propyl)-pyridin-3-ylmethyl-sulfamoyl]-benzamide.
Further examples include: PD 298469, 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-methoxy-5-(4-methyl-piperazine-1-sulfonyl)-benzamide; PD 298470, 2-(2-Chloro-4-iodo-phenylamino)-5-[(2-diethylamino-ethyl)-methyl-sulfamoyl]-3,4-difluoro-N-methoxy-benzamide; PD 298450, 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-methoxy-5-(methyl-prop-2-ynyl-sulfamoyl)-benzamide; PD 298451, 1-[4-(2-Chloro-4-iodo-phenylamino)-2,3-difluoro-5-methoxycarbamoyl-benzenesulfonyl]-piperidine-3-carboxylic acid amide;
PD 298452, 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-methoxy-5-[methyl-(2-pyridin-2-yl-ethyl)-sulfamoyl]-benzamide; PD 298453, 2-(2-Chloro-4-iodo-phenylamino)-5-[(3-dimethylamino-propyl)-methyl-sulfamoyl]-3,4-difluoro-N-methoxy-benzamide; PD 298454, 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-methoxy-5-(4-pyridin-2-yl-piperazine-1-sulfonyl)-benzamide; PD 298455, 5-[Bis-(2-methoxy-ethyl)-sulfamoyl]-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-methoxy-benzamide; PD 298456, 5-[Benzyl-(2-dimethylamino-ethyl)-sulfamoyl]-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-methoxy-benzamide; and PD 298457, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-5-dimethylsulfamoyl-3,4-difluoro-benzamide; PD 298461, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-(methyl-prop-2-ynyl-sulfamoyl)-benzamide; PD 298462, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-[4-(4-fluoro-phenyl)-piperazine-1-sulfonyl]-benzamide; PD 298466, N-Allyloxy-5-[benzyl-(2-dimethylamino-ethyl)-sulfamoyl]-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzamide; PD 298468, 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-(4-methyl-piperazine-1-sulfonyl)-benzamide; and PD 298449, 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-5-(methoxy-methyl-sulfamoyl)-N-(2-morpholin-4-yl-ethoxy)-benzamide.
Particularly preferred compounds include: PD 298458, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-(4-methyl-piperazine-1-sulfonyl)-benzamide; PD 298459, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-(methyl-phenyl-sulfamoyl)-benzamide; PD 298460, 5-(Allyl-methyl-sulfamoyl)-N-allyloxy-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzamide; PD 298463, 1-[5-Allyloxycarbamoyl-4-(2-chloro-4-iodo-phenylamino)-2,3-difluoro-benzenesulfonyl]-piperidine-3-carboxylic acid amide; PD 298464, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-5-[(3-dimethylamino-propyl)-methyl-sulfamoyl]-3,4-difluoro-benzamide; PD 298465, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-(4-pyridin-2-yl-piperazine-1-sulfonyl)-benzamide; and PD 298467, N-Allyloxy-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-5-(methoxy-methyl-sulfamoyl)-benzamide.
C. Synthesis
The disclosed compounds can be synthesized according to the following four Schemes, or variants thereof. These synthetic strategies, which are suitable for conventional or combinatorial synthetic methods, are further exemplified in Examples 1-4 below. 
Amine reagents such as R6R7NH in the schemes above are either commercially available or through straightforward modification of commercially available intermediates. Examples of such amine reagents, which can be reacted with the appropriate intermediate in a combinatorial or matrix method, are provided below. For example, in section B (Compounds), starting at page 8, line 16, there are three sets of thirty (one set each for R5=H, Me, and Cl). The table below provides a number (corresponding to order that the name is found in the text; for example, xe2x80x9c1xe2x80x9d corresponds to compounds 1, 31, and 61 in the list of 90 compounds); the amine reagent name; and a Chemical Abstracts number. Where a PD number is listed, the amine reagent was prepared from commercially available starting materials.
Additional compounds within claim 1 can be made with the following amine reagents. The corresponding CAS number is provided.
Combinatorial Synthesis
The following stock solutions were prepared:
1) An acetonitrile (anhydrous) stock solution 0.05 M in 5-chlorosulfonyl-2,3,4-trifluoro-benzoyl chloride.
2) Acetonitrile (anhydrous) stock solutions 0.05 M in each of the four appropriate hydroxylamine hydrochlorides (see list A) and 0.3 M in 2,6-lutidine.
3) Acetonitrile stock solutions 0.05 M in each of the 25 appropriate amines (see list B). Note that amine salts that were not soluble were also 0.1 M in 2,6-lutidine.
4) Acetonitrile (anhydrous) stock solutions in each of the 3 appropriate anilines (see list C) and 0.88 M in lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran).
An array which treated 4 hydroxylamine hydrochlorides independently with 5-chlorosulfonyl-2,3,4-trifluoro-benzoyl chloride, 25 amines, and 1 aniline was prepared to yield a total of 100 reactions. A liquid handling robot was used to transfer the reagents in such a manner as to insure that all possible combinations were achieved. The appropriate hydroxylamine hydrochloride solution (0.05 mmol, 1 mL) was added to a 2-dram vial, and each vial was treated with 5-chlorosulfonyl-2,3,4-trifluoro-benzoyl chloride solution (0.05 mmol, 1 mL). After 20 minutes the appropriate amine solution (0.05 mmol, 1 mL) was added sequentially. After a further 20 minutes the vials were treated with the solution of 4-iodoaniline (0.055 mmol, 1 mL). The vials were capped and shaken overnight at room temperature. The reactions were quenched with 1 mL of a 1 M aqueous ammonium chloride solution. The vials were concentrated to dryness under a stream of nitrogen and purified by reverse phase HPLC using a 30xc3x97100 mm YMC ODS-A (C18) column. The mobile phase was acetonitrile/water (both with 0.05% trifluoroacetic acid) at 25 mL/min and a linear gradient of 10-100% over 6.5 min and then 3.5 min at 100%, detection was at 214 nm.
An array which treated 4 hydroxylamine hydrochlorides independently with 5-chlorosulfonyl-2,3,4-trifluoro-benzoyl chloride, 25 amines, and 1 aniline was prepared to yield a total of 100 reactions. A liquid handling robot was used to transfer the reagents in such a manner as to insure that all possible combinations were achieved. The appropriate hydroxylamine hydrochloride solution (0.05 mmol, 1 mL) was added to a 2-dram vial, and each vial was treated with 5-chlorosulfonyl-2,3,4-trifluoro-benzoyl chloride solution (0.05 mmol, 1 mL). After 20 minutes the appropriate amine solution (0.05 mmol, 1 mL) was added sequentially. After a further 20 minutes the vials were treated with the solution of 4-iodo-2-methylaniline (0.05 mmol, 0.91 mL). The vials were capped and shaken overnight at room temperature. The reactions were quenched with 1 mL of a 1 M aqueous ammonium chloride solution. The vials were concentrated to dryness under a stream of nitrogen and purified by reverse phase HPLC using a 30xc3x97100 mm YMC ODS-A (C18) column. The mobile phase was acetonitrile/water (both with 0.05% trifluoroacetic acid) at 25 mL/min and a linear gradient of 10-100% over 6.5 min and then 3.5 min at 100%, detection was at 214 nm.
An array which treated 4 hydroxylamine hydrochlorides independently with 5-chlorosulfonyl-2,3,4-trifluoro-benzoyl chloride, 25 amines, and 1 aniline was prepared to yield a total of 100 reactions. A liquid handling robot was used to transfer the reagents in such a manner as to insure that all possible combinations were achieved. The appropriate hydroxylamine hydrochloride solution (0.05 mmol, 1 mL) was added to a 2-dram vial, and each vial was treated with 5-chlorosulfonyl-2,3,4-trifluoro-benzoyl chloride solution (0.05 mmol, 1 mL). After 20 minutes the appropriate amine solution (0.05 mmol, 1 mL) was added sequentially. After a further 20 minutes the vials were treated with the solution of 2-chloro-4-iodoaniline (0.05 mmol, 0.91 mL). The vials were capped and shaken overnight at room temperature. The reactions were quenched with 1 mL of a 1 M aqueous ammonium chloride solution. The vials were concentrated to dryness under a stream of nitrogen and purified by reverse phase HPLC using a 30xc3x97100 mm YMC ODS-A (C18) column. The mobile phase was acetonitrile/water (both with 0.05% trifluoroacetic acid) at 25 mL/min and a linear gradient of 10-100% over 6.5 min and then 3.5 min at 100%, detection was at 214 nm.
List A-Hydroxylamines
1. O-methyl-hydroxylamine
2. O-allyl-hydroxylamine hydrochloride monohydrate (Aldrich)
3. O-cyclopropylmethyl-hydroxylamine hydrochloride
4. O-(2-morpholin-4-yl-ethyl)-hydroxylamine hydrochloride
List B-Amines
1. dimethylamine
2. diethylamine
3. isopropyl-methyl-amine
4. diisopropylamine
5. methylhydrazine
6. 1-methylpiperazine
7. N,N-diethyl-Nxe2x80x2-methylethane-1,2-diamine
8. benzylmethylamine
9. dibenzylamine
10. methyl-phenyl-amine
11. allyl-methyl-amine
12. methyl-prop-2-ynyl-amine
13. methylamino-acetonitrile hydrochloride
14. 1-(4-fluoro-phenyl)-piperazine
15. furan-2-ylmethyl-methyl-amine
16. piperidine-3-carboxylic acid amide
17. methyl-phenethyl-amine
18. methyl-(2-pyridin-2-yl-ethyl)-amine
19. N,N,Nxe2x80x2-trimethyl-propane-1,3-diamine
20. methyl-(1-methyl-piperidin-4-yl)-amine
21. 1-pyridin-2-yl-piperazine
22. bis-(2-methoxy-ethyl)-amine
23. Nxe2x80x2-benzyl-N,N-dimethyl-ethane-1,2-diamine
24. methylamino-acetic acid tert-butyl ester hydrochloride
25. O,N-dimethyl-hydroxylamine hydrochloride
List C-Anilines
1. 4-iodoaniline
2. 2-chloro-4-iodoaniline
3. 4-iodo-2-methylaniline 
D. Uses
The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade. Examples include stroke, heart failure, osteoarthritis, rheumatoid arthritis, organ transplant rejection, and a variety of tumors such as ovarian, lung, pancreatic, brain, prostatic, renal, and colorectal.
1. Dosages
Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of symptoms requiring treatment, and the presence of other medications. In general, an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Capsules, tablets or other formulations (such as liquids and film-coated tablets) may be of between 5 and 200 mg, such as 10, 15, 25, 35, 50 mg, 60 mg, and 100 mg and can be administered according to the disclosed methods.
2. Formulations
Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
3. Related Compounds
The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C1-8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C1-6 alkyl amines and secondary di(C1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C1-3 alkyl primary amines, and di (C1-2 alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C1-7 alkyl, C5-7 cycloalkyl, phenyl, and phenyl(C1-6)alkyl esters. Preferred esters include methyl esters.
The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
Hydroxyl Protecting Groups
Hydroxyl protecting groups include: ethers, esters, and protection for 1,2- and 1,3-diols. The ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups.
Substituted Methyl Ethers
Substituted methyl ethers include: methoxymethyl, methylthiomethyl, t-utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro-ethoxy)methyl, 2-(trimethylsilyl)-ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydro-thiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl.
Substituted Ethyl Ethers
Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, pxe2x80x2-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, xcex1-naphthyldiphenyl-methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4xe2x80x2-bromophenacyloxy)phenyldiphenylmethyl, 4,4xe2x80x2,4xe2x80x3-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4xe2x80x2,4xe2x80x3-tris(levulinoyloxyphenyl) methyl, 4,4xe2x80x2,4xe2x80x3tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-ylmethyl)bis(4xe2x80x2,4xe2x80x3-dimethoxyphenyl)-methyl, 1,1-bis(4-methoxyphenyl)-1xe2x80x2-pyrenylmethyl, 9-anthryl, 9-(9-phenyl) xanthenyl, 9-(9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxy-phenylsilyl.
Esters
Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
Esters
Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate).
Carbonates
Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4-azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2-formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4-(methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
Miscellaneous Esters
In addition to the above classes, miscellaneous esters include: 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, xcex1-naphthoate, nitrate, alkyl N,N,Nxe2x80x2, Nxe2x80x2-tetramethyl-phosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.
Sulfonates
Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
Protection for 1,2- and 1,3-Diols
The protection for 1,2 and 1,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives.
Cyclic Acetals and Ketals
Cyclic acetals and ketals include: methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
Cyclic Ortho Esters
Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, xcex1-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene derivative, xcex1-(N,N-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.
Protection for the Carboxyl Group Esters
Ester protecting groups include: esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters.
Substituted Methyl Esters
Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, xcex1-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters
2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-haloethyl, |-chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2xe2x80x2-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, xcex1-methylcinnamyl, phenyl, p-(methylmercapto)-phenyl, and benzyl.
Substituted Benzyl Esters
Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzo-suberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl.
Silyl Esters
Silyl esters include: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl, and di-t-butylmethylsilyl.
Miscellaneous Derivatives
Miscellaneous derivatives includes: oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaminocobalt(III) complex.
Stannyl Esters
Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl.
Amides and Hydrazides
Amides include: N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides. Hydrazides include: N-phenyl, N,Nxe2x80x2-diisopropyl and other dialkyl hydrazides.
Protection for the Amino Group
Carbamates
Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.
Carbamates
Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydro-thioxanthyl)]methyl, and 4-methoxyphenacyl.
Substituted Ethyl
Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2xe2x80x2-and 4xe2x80x2-pyridyl)ethyl, 2-(N,N-icyclohexylcarboxamido)-ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl.
Assisted Cleavage
Protection via assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl.
Photolytic Cleavage
Photolytic cleavage methods use groups such as: m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.
Urea-Type Derivatives
Examples of of urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative, Nxe2x80x2-p-toluenesulfonylaminocarbonyl, and Nxe2x80x2-phenylaminothiocarbonyl.
Miscellaneous Carbamates
In addition to the above, miscellaneous carbamates include: t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2-dimethoxy-carbonylvinyl, o-(N,N-dimethyl-carboxamido)-benzyl, 1,1-dimethyl-3(N,N-dimethylcarboxamido)propyl, 1,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(pxe2x80x2-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1(p-henylazophenyl)-ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)-benzyl, and 2,4,6-trimethylbenzyl.
Amides
Amides
Amides includes: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridyl-carboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, and N-p-phenylbenzoyl.
Assisted Cleavage
Assisted cleavage groups include: N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (Nxe2x80x2-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxphenyl) propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
Cyclic imide derivatives include: N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenyl-maleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
Special xe2x80x94NH Protective Groups
Protective groups for xe2x80x94NH include: N-alkyl and N-aryl amines, imine derivatives, enamine derivatives, and N-hetero atom derivatives (such as N-metal, N-N,N-P, N-Si, and N-S), N-sulfenyl, and N-sulfonyl.
N-Alkyl and N-Aryl Amines
N-alkyl and N-aryl amines include: N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxyl]-methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine Nxe2x80x2-oxide.
Imine Derivatives
Imine derivatives include: N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, N-(Nxe2x80x2,Nxe2x80x2-dimethylaminomethylene), N,Nxe2x80x2-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenylmethylene, and N-cyclohexylidene.
Enamine Derivative
An example of an enamine derivative is N-(5,5-dimethyl-3-oxo-1-cyclohexenyl).
N-Hetero Atom Derivatives
N-metal derivatives include: N-borane derivatives, N-diphenylborinic acid derivative, N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and N-copper or N-zinc chelate. Examples of N-N derivatives include: N-nitro, N-nitroso, and N-oxide. Examples of N-P derivatives include: N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, and N-diphenyl phosphoryl. Examples of N-sulfenyl derivatives include: N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxy-benzenesulfenyl, N-triphenylmethylsulfenyl, and N-3-nitropyridinesulfenyl.
N-sulfonyl derivatives include: N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4-methoxybenzene-sulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-xcex2-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4-(4xe2x80x2,8xe2x80x2-dimethoxynaphthylmethyl)-benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, and N-phenacylsulfonyl.
Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism. This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
Features of the invention are further described in the examples below.